Andrographolide (C20H30O5) is the diterpene lactone compound extracted from the Acanthaceae plant of Andrographis Paniculata. It is one of the main effective components in the Andrographis Paniculata Nees which is crowned as the natural antibiotic because of its effects of anti-pathogenic microorganism, antipyresis, anti-inflammation, improving body immune, protecting liver by normalizing functioning of the gallbladder and anti-tumor etc. The andrographolide belongs to the diterpene lactone compound. Being an herbal extract, it has advantages of less side effects, better anti-inflammation and extensive source with a competitive price.
Inflammatory bowel disease (IBD) is a recurrent chronic inflammatory disease in the intestinal tract, mainly includes ulcerative colitis (UC) and Crohn's disease (CD). Their definite cause and pathogenesis have not been elucidated and therefore it is still lack of effective treatment methods in clinic. The clinical manifestations of UC include: the intestinal tract injury, most of which firstly appeared in distal colon and sigmoid colon; mainly the left abdomen sustained vague pain or dull pain, which may be relieved after diarrhea; the myxoid-like and pus-blood-like stool accompanied with tenesmus. The clinical manifestations of CD include: mostly abdomen pain; the left abdomen colic pain or spastic sharp pain characterized by paroxysmal occurrence and colic pain mostly occurs post meal; the myxoid-like and watery stool accompanied with constipation alternative with diarrhea. A series of diseases may be more likely to be found in CD than in UC, such as intestinal stenosis, intestinal obstruction, intestinal fistula, intestinal polyp and even carcinogenesis.
Crohn's disease (CD) is identified as one of the IBD. Usually, the symptoms of inflammation, congestion or swollen lymph may occur in the colon, small intestine or stomach of the patient. The main difference between the CD and UC lies in inflammation position and inflammation itself. The Crohn's disease may affect any segment of digestive system, e.g. small intestine, colon, stomach and esophagus, which is common in terminal ileum and adjacent colon segment and right-half colon. UC, however, just occurs in colon and rectum, which is common in rectum and sigmoid colon. Microscopically, the Crohn's disease may affect whole inner wall of bowel, while UC is restricted to mucosa.
Crohn's disease is a chronic and recurrent disease. Effectively therapeutical drugs have not yet been developed for its unknown cause. By now, drugs used for treating Crohn's disease mainly include glucocorticoid, salicylic acid formulations, immunosuppressive agents, antibiotics, methotrexate and biological agents (e.g. infliximab). Although these drugs are proven to be able to change the natural process of disease, they cannot completely alleviate the conditions of disease and decrease the incidence of complications. Moreover, the known western medicines such as glucocorticoid and immunosuppressive agents often cause obvious adverse reaction, and long-term administration will likely result in damage to the body. Hence, we need to develop a new medicine and its formulation thereof for treatment of Crohn's disease.
On the other hand, the colon drug delivery has been regarded as a difficult issue in R&D for a long time, which is determined by colon's own physiological characteristics. It is well-known that the colon is located in the bottom half of the digestive tract, that drugs are very difficult to reach the colon when administrated orally and that enema administration is both inconvenient and painful. As a result of this, the colon targeting preparation technique emerged. Oral colon-specific drug delivery system (OCSDDS) refers to a site-specific drug delivery system, which makes the drug pass through the top half of the digestive tract of stomach and duodenum without any release of the drug, and the medicine is not released until being transferred to ileocecum to demonstrate local or systematic therapeutic effects by a drug delivery technique. The common-used OCSDDS techniques are divided into the pH-dependent type and the enzyme-degraded type.
The pH-dependent OCSDDS is to achieve the colon specific delivery by utilizing the different pH value of each part in human gastrointestinal tract. Usually, the gastric pH value of healthy people is lowest at 1˜3, the duodenum at 4˜6, the jejunum at 6˜7, the ileum at 7˜7.5 and the colon at 7˜8.
Now, the common-used enteric-coating materials have different pH values at which to dissolve. The first type began to dissolve at pH value≧5.5, the second at ≧6.0 and the third at ≧7.0. Up to now, the drug is wrapped by using the third enteric polymer material to coat in the pH-dependent enteric-targeting preparation. It may be achieved that the drug does not release through the top half of the gastrointestinal tract until being transferred to the ileocecum. All Chinese patents (CN1981743, CN101209246, CN103315959) are involved in this technique. As shown in clinical studies, however, gastrointestinal pH values among different individuals are far away from each other. There is a gap between IBD patients and healthy people, and the colon pH value in colitis patients is lower than that in healthy people. As a result, when using this kind of polymer alone, the drug will not be released in vitro and expelled with stool.
As for the enzyme-degraded oral colon-specific delivery of andrographolide, the prior arts include the following steps: coating blank pellet core with the andrographolide to give a drug-loading micropellet; and wrapping said micropellet with a water-insoluble polymer in which mono-saccharides pore-forming agents are contained. The membrane of said polymer does not release in stomach and small intestine until reaching colon. The monosaccharide in the membrane is degraded by colon enzymes to form the pore in the membrane, thereby the drug is gradually dissolved and released. Although this technique has overcome defects of difference among individuals in the pH-dependent OCSDDS, there are some problems. Because the monosaccharide, e.g. Guar gum is dissolved in water and the drug will be soon released from pores formed by dissolution of monosaccharide after entering the body, it is difficult to ensure that effective amount of drug reaches the colon. In addition, the monosaccharide molecule is structurally rigid. Once being embedded among the polymer chains, it will not only affect the extensibility of polymer chain, but also destroy the integrity of polymer membrane, which will make the coating membrane crisped and easily broken. Hence, the risk is increased that the membrane may be early broken during transportation or by gastrointestinal peristalsis. As a result of this, developing new preparations of andrographolide is still needed for treating the IBD.